Ch 20 - Carboxylic Acids and their Derivatives

acetic acid

CH3COOH

methyl group attached to carboxylic acid group

a carboxylic acid responsible for the smell of vinegar

butanoic acid

CH3CH2CH2COOH

propyl group attached to carboxylic acid group (the C in the carboxylic acid group counts as the 4th C)

a carboxylic acid responsible for the rancid odor of sour butter

hexanoic acid

CH3CH2CH2CH2CH2COOH

pentyl group attached to carboxylic group (the C of the COOH makes the 6th C)

a carboxylic acid responsible for the odor of dirty socks

lactic acid

CH3CHOHCOOH

a carboxylic acid responsible for the taste of sour milk

nomenclature of monocarboxylic acids

name parent as the longest chain that includes the C of the carboxylic acid group (that C is assigned locant number 1)

suffix “-oic acid”

if the carboxylic acid is connected to a ring, the compound is named as an alkane carboxylic acid (e.g. cyclohexanecarboxylic acid)

formic acid

common name for methanoic acid

acetic acid

common name for ethanoic acid

propionic acid

common name for propanoic acid

butyric acid

common name for butanoic acid

benzoic acid

common name for benzenecarboxylic acid

nomenclature for diacids

use suffix “dioic acid”

same rules apply as usual for choosing parent, assigning locants, and naming substituents

oxalic acid

common name for ethanedioic acid

malonic acid

common name for propanedioic acid

succinic acid

common name for butanedioic acid

glutaric acid

common name for pentanedioic acid

structure and properties of carboxylic acids

sp2 hybridized C → trigonal planar geometry

can form 2 H-bonding interactions (between carbonyl O of one and H of the other); molecules can associate with each other in pairs

relatively high boiling point

mildly acidic; treatment with a strong bae (e.g. NaOh) yields a carboxylate salt

pKa usually between 4 and 5

very weak acids when compared to inorganic acids, but relatively acidic compared to most organic compounds

physiological pH

the pH of blood

~7.3

at this pH, carboxylate ion to carboxylic acid ratio is ~1000:1 (figured because of rearrangement of Henderson-Hasselbalch equation)

Henderson-Hasselbalch equation

pH = pKa + log([conjugate base]/[acid])

effect of substituents on acidity

pKa of acetic acid = 4.8

if 1 Cl added, pKa = 2.9 (at alpha position)

if 2 Cl added, pKa = 1.3 (at alpha position)

if 3 Cl added, 0.9 (at alpha position)

^because of inductive effects of Cl → stabilize the conjugate base

if 1 Cl added at beta position, pKa = 4.1

if 1 Cl added at gamma position, pKa = 4.5

pKa of benzoic acid with para-substituted NO2

3.4

NO2 is substituted at the Z

pKa of benzoic acid with para-substituted CHO

3.8

CHO is substituted at the Z

pKa of benzoic acid with para-substituted Cl

4.0

Cl is substituted at the Z

pKa of benzoic acid with para-substituted H

4.2

H is substituted at the Z

pKa of benzoic acid with para-substituted CH3

4.3

CH3 is substituted at the Z

pKa of benzoic acid with para-substituted OH

4.5

OH is substituted at the Z

oxidative cleavage of alkynes

a way to prepare carboxylic acids

alkyne gets treated with 1) O3 and 2) H2O

oxidation of primary alcohols

a way to prepare a carboxylic acid

primary alcohol is treated with Na2Cr2O7, H2SO4, H2O

yields 1 carboxylic acid

various strong oxidizing agents can be used

oxidation of alkylbenzenes

an alkylbenzene is treated with Na2Cr2O7, H2SO4, H2O

alkyl group is completely oxidized, as long as the benzylic position is not quaternary

yields 1 carboxylic acid

hydrolysis of nitriles

a way to prepare a carboxylic acid

a nitrile is treated with aqueous acid

produces 1 carboxylic acid

carboxylation of Grignard reagents

a way to prepare a carboxylic acid

Grignard reagent is treated with carbon dioxide and acid

yields 1 carboxylic acid

process of carboxylation of Grignard reagents

Grignard reagent (Nuc) attacks electrophilic center of CO2 → generates carboxylate ion

carboxylate gets protonated to yield carboxylic acid

2 steps occur separately

reduction of carboxylic acid with LAH

carboxylic acid gets treated with 1) LiAlH4 and 2) H3O+

produces alcohol

reduction of carboxylic acid with borane

carboxylic acid is treated with BH3 and THF

produces alcohol

reduction with LAH vs BH3

reduction with borane is often preferred over with LAH

borane reacts selectively with carboxylic acid group in the presence of another carbonyl group; LAH is so strong it reduces both carbonyls

carboxylic acid derivatives

compounds that are similar in structure to a carboxylic acid (RCOOH) but the OH has been replaced with a different group, Z

Z is a heteroatom, e.g. Cl, O, N, etc.

nitriles (R-CN) are also derivatives because they have the same oxidation state as carboxylic acids

acid halide

a carboxylic acid derivative in which the OH of RCOOH has been replaced by a halogen (e.g. Cl)

full structure is RCOX (X = halogen)

highly reactive; not very common in nature

acid anhydride

a carboxylic acid derivative in which the OH of RCOOH has been replaced by OCOR

full structure is RCOOCOR

highly reactive; not very common in nature

ester

a carboxylic acid derivative in which the OH of RCOOH has been replaced by OR

full structure is RCOOR

more stable than acid halides and acid anhydrides

abundant in nature; often have pleasant odors and contribute to the aromas of fruits and flowers

amide

a carboxylic acid derivative in which the OH of RCOOH has been replaced by NH2

full structure is RCONH2

abundant in living organisms

e.g. repeating linkages make up proteins

nitrile

a carboxylic acid derivative with the same oxidation state as a carboxylic acid; C has three bonds to a heteroatom (N)

conversion of nitrile to carboxylic acid, or vice versa, is neither reduction or oxidation

structure is RCN

nomenclature of acid halides

replace suffix “ic acid” with “yl halide”

e.g. acetic acid → acetyl bromide

e.g. benzoic acid → benzoyl chloride

e.g. cyclohexanecarboxylic acid → cyclohexanecarbonyl chloride

nomenclature of acid anhydrides

replace suffix “acid” with “anhydride”

unsymmetrical anhydrides are prepared from two different carboxylic acids; named by indicating both acids alphabetically followed by suffix “anhydride”

e.g. acetic acid → acetic anhydride

e.g. succinic acid → succinic anhydride

e.g. acetic benzoic anhydride

nomenclature of esters

indicate the alkyl group attached to the oxygen first

follow with carboxylic acid, and replace suffix “ic acid” with “ate”

see picture for examples

nomenclature of amides

replace suffix “ic acid” or “oic acid” with “amide”

e.g. acetic acid → acetamide

e.g. benzoic acid → benzamide

if connected to a ring, suffix “carboxylic acid” is replaced with “carboxamide”

if N atom bears alkyl groups, the groups are connected at the beginning of the name and the letter “N'“ is used as a locant instead of a number

nomenclature of nitriles

replace suffix “ic acid” or “oic acid” with “onitrile”

e.g. acetic acid → acetonitrile

e.g. benzoic acid → benzonitrile

relative order of reactivity of carboxylic acid derivatives

listed from least to most reactive

amide, ester, acid anhydride, acid halide

reactivity of carboxylic acid derivatives (in general)

similar to reactivity of aldehydes and ketones

carbonyl group is electrophilic; subject to nucleophilic attack

heteroatom can function as a leaving group (unlike ketones and aldehydes)

nucleophilic acyl substitution

a reaction in which a nucleophile attacks a carboxylic derivative

nucleophile replaces the Z leaving group

note: most reactions in this chapter are variants of this type of reaction

mechanism for nucleophilic acyl substitution

nucleophilic attack: forms tetrahedral intermediate

loss of leaving group and carbonyl reformation

note: even poor leaving groups (e.g. RO-) can be expelled

NOT Sn2 (not concerted) because Sn2 does not happen readily at sp2-hybridized centers

proton transfer may happen either 1) before nucleophilic attack, 2) before loss of leaving group, or 3) at the end of the mechanism. May happen at all three steps, may only happen at one. Depends on conditions

preparation of acid chlorides

carboxylic acid is treated with thionyl chloride (SOCl2)

yields an acid chloride + SO2 + HCl

mechanism for the preparation of acid chloride via thionyl chloride

part 1:

nucleophilic attack: carboxylic acid functions as Nuc

loss of leaving group: Cl- is expelled

proton transfer: deprotonation

results in a molecule with OSOCl, an excellent leaving group

part 2:

nucleophilic attack: Cl- is Nuc, attacks carbonyl

loss of leaving group

rearrangement of product to make SO2 and Cl-

hydrolysis of acid chloride

acid chloride is treated with water

yields carboxylic acid

mechanism for hydrolysis of an acid chloride

nucleophilic attack: water is Nuc

loss of leaving group: carbonyl reforms, Cl- is expelled

proton transfer: deprotonation

pyridine may be used to remove HCl as it is produced, because HCl can often react with other functional groups in the compound (unwanted)

alcoholysis of acid chlorides

acid chloride is treated with alcohol

converts acid chloride into ester

mechanism is directly analogous to mechanism for hydrolysis of an acid chloride

pyridine is used, again

acylation of an alcohol

alcohol is treated with acyl chloride and pyridine

yields ester

selective for primary alcohols in the presence of secondary alcohols

aminolysis of acid chlorides

acid chloride is treated with 2 equivalents of ammonia

produces an amide

pyridine is not used because ammonia is a strong enough base to neutralize HCl as it is produced (this is why a second equivalent is needed)

analogous mechanism to hydrolysis; nucleophilic attack, loss of leaving group, proton transfer

aminolysis of acid chlorides with amines

primary or secondary amines can be used instead of ammonia

N-substituted amides are produced

same process as regular aminolysis

reduction of acid chlorides

acid chloride is treated with LiAlH4

reduced to give alcohol

2 steps are required (acidic workup is needed)

mechanism for reduction of an acid chloride with LAH

nucleophilic attack: LiAlH4 delivers a hydride ion nucleophile

loss of leaving group: Cl- is expelled

second nucleophilic attack: again, by a hydride

proton transfer: protonation

conversion of acid chloride into aldehyde

acid chloride is treated with 1) LiAl(OR)3H and 2) H3O+ to produce aldehyde

reacts with acid chloride rapidly and with aldehyde more slowly

allows aldehyde to be isolated

addresses the issue of using one equivalent of LiAlH4

reaction between acid chloride and organometallic reagents

acid chloride is treated with a Grignard reagent (in excess)

converts acid chloride into alcohol; two alkyl groups are introduced

2 steps are needed

mechanism for reaction between an acid chloride and a Grignard reagent

nucleophilic attack: Grignard reagent is Nuc

loss of leaving group: Cl- is expelled (produces a ketone)

second nucleophilic attack: another Grignard reagent attacks carbonyl (produces an alkoxide ion)

proton transfer: protonation

acid chloride conversion to ketone

Grignard reagent cannot be used; not selective enough to make a ketone

more selective reagent, like Gilman reagent, is needed

Gilman reagent

a lithium dialkyl cuprate (R2CuLi)

used to convert an acid chloride into a ketone

similar to a Grignard reagent, but more selective

conversion of acetic acid into an acid anhydride

acetic acid is excessively heated (800*C) to convert into an acid anhydride and water

only practical for acetic acid because most other acids cannot survive the heat

conversion of carboxylic acids into acid anhydrides (not excessive heating)

acid chloride is treated with carboxylate ion

carboxylate functions as a nucleophile

prepares an acid anhydride

can produce symmetrical or unsymmetrical anhydrides

mechanism of acid chloride to acid anhydride conversion

nucleophilic attack

loss of leaving group: Cl- is expelled

reactions of acid anhydrides

reaction mechanisms are analogous to reactions of acid chlorides, except the leaving group is different

leaving group is a carboxylate ion

pyridine is not needed, because HCl is not produced

not as efficient as starting materials (when compared to acid chlorides) because of poor atom anatomy (half of the starting material is lost)

acetylation with acetic anhydride

an alcohol or amine is often acetylated with acetic anhydride

these reactions are used in preparation of aspirin and tylenol

preparation of esters

carboxylic acid is treated with 1) strong base and 2) alkyl halide

carboxylic acid is deprotonated → yields carboxylate ion, which functions as nucleophile and attacks alkyl halide

Sn2 process

tertiary alkyl halides cannot be used

Fischer esterification

carboxylic acid is treated with alcohol in the presence of an acid catalyst

produces an ester

reversible

ester formation can be favored by either using excess of alcohol (use alcohol as solvent) or by removing water from reaction mixture as it is formed

mechanism for Fischer esterification

proton transfer: carbonyl is protonated (makes it more electrophilic)

nucleophilic attack: alcohol is Nuc

proton transfer: deprotonation

proton transfer: OH is protonated

loss of leaving group: H2O is expelled

proton transfer: carbonyl is deprotonated

ester preparation via acid chloride

acid chloride is treated with alcohol

prepares an ester

saponification

base-catalyzed hydrolysis of an ester

ester is treated with 1) NaOH and 2) an acid

converts ester into carboxylic acid

this process is used to make soap

mechanism for saponification

nucleophilic attach: OH- is nucleophile

loss of leaving group: OR- is expelled, carbonyl reforms

proton transfer: deprotonation

acid-catalyzed hydrolysis of esters

ester is treated with acid

produces carboxylic acid

mechanism for acid-catalyzed hydrolysis of esters

proton transfer: protonation of carbonyl

nucleophilic attack: water is nucleophile

proton transfer: deprotonation of H2O

proton transfer: protonation of alkoxy group

loss of leaving group: MeOH is expelled

proton transfer: deprotonation

aminolysis of esters

ester is treated with amine, reacts slowly

yields amides

little practical utility, because amide preparation is achieved more efficiently from reaction between acid chlorides and ammonia (or 1* or 2* amines)

ester reduction with hydride-reducing agents

ester is treated with LAH

yields alcohol

mechanism for ester reduction with LAH

nucleophilic attack: LiAlH4 delivers hydride ion (Nuc)

loss of leaving group: OMe is expelled

second nucleophilic attack: another hydride attacks

proton transfer: protonation

ester reduction with DIBAH

ester is treated with 1) DIBAH and 2) HO+

yields aldehyde

performed at low temperature to prevent further reduction of the aldehyde

used to prevent further reduction that would happen if LAH was used

reaction between ester and Grignard reagents

ester is treated with 1) excess RMgBr and 2) H3O+

yields alcohol with two alkyl groups introduced

mechanism for reaction between an ester and Grignard reagent

nucleophilic attack: Grignard reagent is Nuc

loss of leaving group: OMe is expelled

second nucleophilic attack: another Grignard reagent attacks

proton transfer: protonation

amide preparation

amides can be made from any carboxylic acid (except nitriles)

most efficient preparation is from acid chloride, treated with 2 equivalents of NH3

(acid halides are best starting material because acid halides are the most reactive derivative)

acid-catalyzed hydrolysis of amides

amide is hydrolyzed in the presence of aqueous acid

gives carboxylic acid

process is slow and requires heating

ammonium ion (NH4+) is formed as a byproduct; much weaker than H3O+ (pKa 9.2 vs -1.7)

equilibrium greatly favors product formation → process is effectively irreversible

mechanism for acid-catalyzed hydrolysis of an amide

proton transfer: protonation of carbonyl

nucleophilic attack: water is Nuc

proton transfer: deprotonation of H2O

proton transfer: protonation of amino group

loss of leaving group: NH3 is expelled

proton transfer: deprotonation

amide hydrolysis under basic conditions

amide is treated with 1) NaOH, heat and 2) H3O+

process is very slow; analogous to mechanism for ester saponification

mechanism for hydrolysis of amides under basic conditions

nucleophilic attack: OH- is Nuc

loss of leaving group: NH2 is expelled

proton transfer: deprotonation

amide reduction

amide is treated with excess LAH and followed by aqueous workup

treated with 1) xs LiAlH4 and 2) H2O

different from most other reactions: carbonyl is completely removed

workup is different; H2O is used instead of H3O+ because amines get protonated in the presence of H3O+ to give RNH3+ ions (protonating the amine should be avoided)

nitrile preparation via Sn2

alkyl halide is treated with cyanide ion (NaCN)

yields nitrile

Sn2 mechanism

tertiary alkyl halides cannot be used

dehydration of amides

prepares nitrile from amide

amide is treated by SOCl2 or other reagents

benefit: can prepare tertiary nitriles, which cannot be prepared via Sn2

mechanism for dehydration of amides

nucleophilic attack: amide is Nuc

loss of leaving group: Cl- is expelled

proton transfer: positive charge on N is removed via deprotonation by base

proton transfer: eliminates proton and a leaving group

hydrolysis of nitriles

nitrile is hydrolyzed in aqueous acidic condition

yields amide

further hydrolysis yields carboxylic acid

mechanism for acid-catalyzed hydrolysis of nitriles

proton transfer: nitrile is protonated

nucleophilic attack: water is nucleophile

proton transfer: deprotonation removes positive charge

proton transfer: protonation to make intermediate

resonance rearrangement of intermediate

proton transfer: deprotonation

base-catalyzed hydrolysis of nitrile

nitrile is treated with 1) NaOH, H2O and 2) H3O+

nitrile is hydrolyzed in aqueous base; converted to amide then carboxylic acid

mechanism for base-catalyzed hydrolysis of nitriles

nucleophilic attack: OH- is nucleophile

proton transfer: protonation

proton transfer: deprotonation

resonance rearrangement

proton transfer: protonation

reaction between nitrile and Grignard reagent

Grignard reagent attacks nitrile

resulting anion is treated with aqueous acid → gives imine

imine is hydrolyzed to ketone under acidic conditions

reduction of nitriles

nitrile is treated with 1) xs LiAlH4 and 2) H2O

yields amine

important to use H2O for workup instead of H3O+ to avoid protonation of amine

IR signal for an acid chloride carbonyl

~1790 cm-1

IR signals for an acid anhydride carbonyls

1760 and 1820 cm-1

two signals